Prevalence and Risk Factors for Methicillin-Resistant Staphylococcus aureus in an HIV-Positive Cohort

Background: Persons living with HIV (PLWH) are disproportionately burdened with methicillin-resistant Staphylococcus aureus (MRSA). Our objective was to evaluate prevalence and risks for MRSA colonization in PLWH. Methods: Adults were recruited from Johns Hopkins University AIDS Service in Baltimore, Maryland. A risk questionnaire and specimen collection from anatomic sites with culture susceptibility and genotyping were completed. Generalized estimating equation modeling identified MRSA colonization risk factors. Results: Of 500 participants,mostwere black (69%), on antiretroviral therapy (ART) (87%),with undetectable viral loads (73.4%). Median CD4 count was 487 cells/mm3 (interquartile range, 316-676.5 cells/mm3). MRSA prevalence was 15.4%, predominantly from the nares (59.7%). Forty percent were nares negative but were colonized elsewhere. Lower odds for colonizationwere associatedwith recent sexual activity (adjusted odds ratio [AOR]¼0.84, P$75,000; AOR ¼ 2.68, P \u3c .001), recent hospitalization (AOR ¼ 1.54, P \u3c .001), incarceration (AOR ¼ 1.55,

Prevalence and Risk Factors for Methicillin-Resistant Staphylococcus aureus in an HIV-Positive Cohort

Background: Persons living with HIV (PLWH) are disproportionately burdened with methicillin-resistant Staphylococcus aureus (MRSA). Our objective was to evaluate prevalence and risks for MRSA colonization in PLWH. Methods: Adults were recruited from Johns Hopkins University AIDS Service in Baltimore, Maryland. A risk questionnaire and specimen collection from anatomic sites with culture susceptibility and genotyping were completed. Generalized estimating equation modeling identified MRSA colonization risk factors. Results: Of 500 participants,mostwere black (69%), on antiretroviral therapy (ART) (87%),with undetectable viral loads (73.4%). Median CD4 count was 487 cells/mm3 (interquartile range, 316-676.5 cells/mm3). MRSA prevalence was 15.4%, predominantly from the nares (59.7%). Forty percent were nares negative but were colonized elsewhere. Lower odds for colonizationwere associatedwith recent sexual activity (adjusted odds ratio [AOR]¼0.84, P$75,000; AOR ¼ 2.68, P \u3c .001), recent hospitalization (AOR ¼ 1.54, P \u3c .001), incarceration (AOR ¼ 1.55,

The neuroblast and angioblast chemotaxic factor SDF-1 (CXCL12) expression is briefly up regulated by reactive astrocytes in brain following neonatal hypoxic-ischemic injury

BACKGROUND: Stromal cell-derived factor 1 (SDF-1 or CXCL12) is chemotaxic for CXCR4 expressing bone marrow-derived cells. It functions in brain embryonic development and in response to ischemic injury in helping guide neuroblast migration and vasculogenesis. In experimental adult stroke models SDF-1 is expressed perivascularly in the injured region up to 30 days after the injury, suggesting it could be a therapeutic target for tissue repair strategies. We hypothesized that SDF-1 would be expressed in similar temporal and spatial patterns following hypoxic-ischemic (HI) injury in neonatal brain. RESULTS: Twenty-five 7-day-old C57BL/J mice underwent HI injury. SDF-1 expression was up regulated up to 7 days after the injury but not at the later time points. The chief sites of SDF-1 up regulation were astrocytes, their foot processes along blood vessels and endothelial cells. CONCLUSION: The localization of SDF-1 along blood vessels in the HI injury zone suggests that these perivascular areas are where chemotaxic signaling for cellular recruitment originates and that reactive astrocytes are major mediators of this process. The associated endothelium is likely to be the site for vascular attachment and diapedesis of CXCR4 receptor expressing cells to enter the injured tissue. Here we show that, relative to adults, neonates have a significantly smaller window of opportunity for SDF-1 based vascular chemotaxic recruitment of bone marrow-derived cells. Therefore, without modification, following neonatal HI injury there is only a narrow period of time for endogenous SDF-1 mediated chemotaxis and recruitment of reparative cells, including exogenously administered stem/progenitor cells

A general approach for the site-selective modification of native proteins, enabling the generation of stable and functional antibody-drug conjugates.

Antibody-drug conjugates (ADCs) are a class of targeted therapeutics that utilize the specificity of antibodies to selectively deliver highly potent cytotoxins to target cells. Although recent years have witnessed significant interest in ADCs, problems remain with the standard linkage chemistries used for cytotoxin-antibody bioconjugation. These typically (1) generate unstable constructs, which may lead to premature cytotoxin release, (2) often give a wide variance in drug-antibody ratios (DAR) and (3) have poor control of attachment location on the antibody, resulting in a variable pharmacokinetic profile. Herein, we report a novel divinylpyrimidine (DVP) linker platform for selective bioconjugation via covalent re-bridging of reduced disulfide bonds on native antibodies. Model studies using the non-engineered trastuzumab antibody validate the utility of this linker platform for the generic generation of highly plasma-stable and functional antibody constructs that incorporate variable biologically relevant payloads (including cytotoxins) in an efficient and site-selective manner with precise control over DAR. DVP linkers were also used to efficiently re-bridge both monomeric and dimeric protein systems, demonstrating their potential utility for general protein modification, protein stabilisation or the development of other protein-conjugate therapeutics.AstraZeneca, Cambridge Trusts, EPSRC, BBSRC, Royal Society, MR

Supernova Limits on the Cosmic Equation of State

We use Type Ia supernovae studied by the High-Z Supernova Search Team to constrain the properties of an energy component which may have contributed to accelerating the cosmic expansion. We find that for a flat geometry the equation of state parameter for the unknown component, alpha_x=P_x/rho_x, must be less than -0.55 (95% confidence) for any value of Omega_m and is further limited to alpha_x<-0.60 (95%) if Omega_m is assumed to be greater than 0.1 . These values are inconsistent with the unknown component being topological defects such as domain walls, strings, or textures. The supernova data are consistent with a cosmological constant (alpha_x=-1) or a scalar field which has had, on average, an equation of state parameter similar to the cosmological constant value of -1 over the redshift range of z=1 to the present. Supernova and cosmic microwave background observations give complementary constraints on the densities of matter and the unknown component. If only matter and vacuum energy are considered, then the current combined data sets provide direct evidence for a spatially flat Universe with Omega_tot=Omega_m+Omega_Lambda = 0.94 +/- 0.26 (1-sigma).Comment: Accepted for publication in ApJ, 3 figure

Proportions of bird damage in tree fruits are higher in low-fruit-abundance contexts

Frugivorous birds impose significant costs on tree fruit growers through direct consumption of fruit and grower efforts to manage birds.We documented factors that influenced tree fruit bird damage from 2012 through 2014 with a coordinated field study in Michigan, New York, and Washington. For sweet cherries, percent bird damage was higher in 2012 compared to 2013 and 2014, in Michigan and New York compared toWashington, and in blocks with more edges adjacent to non-sweet cherry land-cover types. These patterns appeared to be associated with fruit abundance patterns; 2012 was a particularly lowyield year for tree fruits in Michigan and New York and percent bird damage was high. In addition, percent bird damage to sweet and tart cherries in Michigan was higher in landscapes with low to moderate forest cover compared to higher forest cover landscapes. \u27Honeycrisp\u27 apple blocks under utility wires were marginally more likely to have greater bird damage compared to blocks without wires. We recommend growers prepare bird management plans that consider the spatial distribution of fruit and non-fruit areas of the farm. Growers should generally expect to invest more in bird management in low-yield years, in blocks isolated from other blocks of the same crop, and in blocks where trees can provide entry to the crop for frugivorous birds

Prospective, randomized evaluation of a personal digital assistant-based research tool in the emergency department

Background Personal digital assistants (PDA) offer putative advantages over paper for collecting research data. However, there are no data prospectively comparing PDA and paper in the emergency department. The aim of this study was to prospectively compare the performance of PDA and paper enrollment instruments with respect to time required and errors generated. Methods We randomized consecutive patients enrolled in an ongoing prospective study to having their data recorded either on a PDA or a paper data collection instrument. For each method, we recorded the total time required for enrollment, and the time required for manual transcription (paper) onto a computer database. We compared data error rates by examining missing data, nonsensical data, and errors made during the transcription of paper forms. Statistical comparisons were performed by Kruskal-Wallis and Poisson regression analyses for time and errors, respectively. Results We enrolled 68 patients (37 PDA, 31 paper). Two of 31 paper forms were not available for analysis. Total data gathering times, inclusive of transcription, were significantly less for PDA (6:13 min per patient) compared to paper (9:12 min per patient; p < 0.001). There were a total of 0.9 missing and nonsense errors per paper form compared to 0.2 errors per PDA form (p < 0.001). An additional 0.7 errors per paper form were generated during transcription. In total, there were 1.6 errors per paper form and 0.2 errors per PDA form (p < 0.001). Conclusion Using a PDA-based data collection instrument for clinical research reduces the time required for data gathering and significantly improves data integrity

ELF5 modulates the estrogen receptor cistrome in breast cancer.

Acquired resistance to endocrine therapy is responsible for half of the therapeutic failures in the treatment of breast cancer. Recent findings have implicated increased expression of the ETS transcription factor ELF5 as a potential modulator of estrogen action and driver of endocrine resistance, and here we provide the first insight into the mechanisms by which ELF5 modulates estrogen sensitivity. Using chromatin immunoprecipitation sequencing we found that ELF5 binding overlapped with FOXA1 and ER at super enhancers, enhancers and promoters, and when elevated, caused FOXA1 and ER to bind to new regions of the genome, in a pattern that replicated the alterations to the ER/FOXA1 cistrome caused by the acquisition of resistance to endocrine therapy. RNA sequencing demonstrated that these changes altered estrogen-driven patterns of gene expression, the expression of ER transcription-complex members, and 6 genes known to be involved in driving the acquisition of endocrine resistance. Using rapid immunoprecipitation mass spectrometry of endogenous proteins, and proximity ligation assays, we found that ELF5 interacted physically with members of the ER transcription complex, such as DNA-PKcs. We found 2 cases of endocrine-resistant brain metastases where ELF5 levels were greatly increased and ELF5 patterns of gene expression were enriched, compared to the matched primary tumour. Thus ELF5 alters ER-driven gene expression by modulating the ER/FOXA1 cistrome, by interacting with it, and by modulating the expression of members of the ER transcriptional complex, providing multiple mechanisms by which ELF5 can drive endocrine resistance

Constraints on growth index parameters from current and future observations

We use current and future simulated data of the growth rate of large scale structure in combination with data from supernova, BAO, and CMB surface measurements, in order to put constraints on the growth index parameters. We use a recently proposed parameterization of the growth index that interpolates between a constant value at high redshifts and a form that accounts for redshift dependencies at small redshifts. We also suggest here another exponential parameterization with a similar behaviour. The redshift dependent parametrizations provide a sub-percent precision level to the numerical growth function, for the full redshift range. Using these redshift parameterizations or a constant growth index, we find that current available data from galaxy redshift distortions and Lyman-alpha forests is unable to put significant constraints on any of the growth parameters. For example both $\Lambda$CDM and flat DGP are allowed by current growth data. We use an MCMC analysis to study constraints from future growth data, and simulate pessimistic and moderate scenarios for the uncertainties. In both scenarios, the redshift parameterizations discussed are able to provide significant constraints and rule out models when incorrectly assumed in the analysis. The values taken by the constant part of the parameterizations as well as the redshift slopes are all found to significantly rule out an incorrect background. We also find that, for our pessimistic scenario, an assumed constant growth index over the full redshift range is unable to rule out incorrect models in all cases. This is due to the fact that the slope acts as a second discriminator at smaller redshifts and therefore provide a significant test to identify the underlying gravity theory.Comment: 13 pages, 5 figures, matches JCAP accepted versio